Descripción del proyecto
Estudio del mecanismo de agregación de proteínas en los trastornos neurodegenerativos
Las células realizan la mayoría de los procesos bioquímicos en orgánulos con o sin membrana. Pruebas recientes indican que la separación de fases líquido-líquido constituye el principal mecanismo que conlleva que las proteínas formen orgánulos sin membrana. El equipo del proyecto InMIND, financiado con fondos europeos, se propone comprender la relación de esta separación con los trastornos neurodegenerativos, en los que proteínas intrínsecamente desordenadas forman agregados insolubles y provocan disfunción y muerte neuronal. Su trabajo permitirá dilucidar los determinantes moleculares de la separación de fases líquido-líquido, así como seleccionar micromoléculas que impiden la formación de condensados biomoleculares, lo que posibilitará el desarrollo de nuevas estrategias terapéuticas para los trastornos neurodegenerativos.
Objetivo
With population ageing and the lack of effective treatments, neurodegenerative diseases (NDs) are expected to pose an increasingly severe challenge to healthcare systems worldwide. A hallmark of NDs is the presence of insoluble aggregates of intrinsically disordered proteins (IDPs) and proteins with disordered regions in neuronal cells. Growing evidence suggests that these disease-associated proteins condense into liquid-like droplets through liquid-liquid phase separation (LLPS). Dysregulation of this process results in the maturation of the liquid-like droplet into a dynamically arrested state, promoting the formation of putatively neurotoxic oligomers and amyloid fibrils.
In this project, I will first develop a molecular model that accurately predicts LLPS of IDPs from amino acid sequence and solution conditions. Second, through large-scale simulations of IDPs, I will elucidate the influence of mutations and post-translational modifications on the material properties of protein condensates. Third, I will employ the model to identify small molecules that preferentially partition into the protein-dense phase and enhance the dynamics of the protein network of the condensate. My findings will shed light on the molecular determinants of LLPS and contribute to explore an innovative therapeutic strategy for NDs, wherein small-molecule compounds prevent aberrant liquid-to-hydrogel-like transitions of biomolecular condensates. The project will enable me to apply my expertise in physical chemistry to therapeutically-relevant biological systems, acquire new competencies in chemoinformatics and project management, and establish myself as a high-quality researcher in the field of biomolecular condensates. The group of Prof. Kresten Lindorff-Larsen in the SBiN-Lab section at the University of Copenhagen will provide an excellent environment with world-leading experts in integrative structural biology and biophysics.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
1165 Kobenhavn
Dinamarca